The present invention relates to nanodevices. More particularly, the invention relates to a nanodevice incorporating a targeting protein which delivers a drug to a predetermined destination.
Out of convenience, many small molecule drugs are administered systemically, generally orally or by injection into the circulatory system. Both of these methods have disadvantages. In the case of oral administration, the drug must be able to remain intact in the highly acidic environment of the stomach (or metabolized from its administered form to its active form), then be absorbed into the bloodstream and circulate until it reaches its target. Injection removes the concerns associated with the digestive system but still requires a large dose that is given in a nonspecific fashion. As a result of these large doses, drug receptors in cells and tissues that are not the intended target for treatment are exposed to the drug, frequently causing undesired side effects. For instance, an inhibitor of mitosis that is administered systemically in order to minimize tumor growth will also inhibit mitosis in healthy cells which are replicating.
One condition which would particularly benefit from targeted drug treatment is cervical spinal cord injury. When injury occurs rostral to the phrenic nucleus, the descending bulbospinal respiratory pathways can become disrupted and the result can be a life-threatening weakness of respiratory muscle function, leading to increased deaths in this patient population from pneumonia, pulmonary emboli, and septicemia. These mortality factors may be caused directly by the weakening of the respiratory muscles after SCI or indirectly by the need to place patients on long-term mechanical ventilator support. Cervical spinal cord injury (SCI) patients dependent on ventilators experience respiratory system complications which are a major cause of re-hospitalization and death. Increasing respiratory output with pharmaceutical intervention could eliminate ventilator dependence and reduce respiratory complications.
The primary descending respiratory drive, provided by the bulbospinal pathway, transmits an excitatory impulse from the rostral ventral respiratory groups (rVRGs) in the medulla to the phrenic nuclei (PN) in the cervical spinal cord (C3-C6). The phrenic nuclei then stimulate the diaphragm muscle via the phrenic nerves resulting in contraction of the diaphragm to take a breath. Following a hemisection at the second cervical segment (C2Hx) the ipsilateral hemidiaphragm is paralyzed due to the disruption of the rVRG axons descending to the ipsilateral PN. The inability of the ipsilateral hemidiaphragm to contract results in respiratory stress and can lead to many related maladies over time. However, the crossed phrenic pathway, functionally latent in non-injured individuals, decussates caudal to the hemisection. Pharmaceutical intervention such as systemically administered theophylline can stimulate the cross phrenic pathway and restore function to the hemidiaphragm. Unfortunately in humans systemically administered theophylline at a therapeutic dose produces many unwanted side effects. In order to eliminate the side effects of theophylline while still maintaining the ability to stimulate the crossed phrenic pathway, theophylline will be bound to a nanoconjugate to selectively target only those neurons in the respiratory motor pathway. Injection of the nanoconjugate into the paralyzed hemidiaphragm immediately after a C2Hx will induce functional recovery of the diaphragm in the acute C2Hx injury model.
One class of drug that is used to treat the respiratory system is methylxanthines. These drugs are thought to assist with respiration by causing smooth muscle to dilate, thereby allowing constricted airways to open. The drugs have also been shown to induce recovery of diaphragm muscle paralyzed by spinal cord injury in both animals and humans. Among the drugs of this class are theophylline (THP), dyphylline, and aminophylline. Although effective, these drugs can also cause side effects such as nausea, chest pain, irregular heartbeat, and light headedness when delivered in such a way that they act systemically. In spinal cord injured patients, they can also cause insomnia and excessive nervousness. Because of these effects, the patients often cannot tolerate systemic drug therapy.
It has been a challenge to develop methods of and vehicles for delivering drugs to specific areas in the body.